The study of expertise has led to insight into the nature of expert performance in a variety of problem solving domains. In medicine, considerable study has focused on diagnostic reasoning, however the role of expertise in coping with decision complexity has remained to be more fully explored. In this thesis three groups of subjects, consisting of medical students (novices), residents (intermediates) and intensive care experts were each presented with complex cases of intensive care problems containing varying levels of uncertain and conflicting evidence. The subjects were asked to think-aloud as they worked through the problems and provided a management and treatment plan for each case. The audiotaped protocols were coded for key process variables in decision making and problem solving. / The results indicate that the strategies used by novices, intermediates and experts for dealing with complex cases containing ambiguous information varied considerably. When faced with anomalous evidence, expert physicians were found to disregard the anomalous evidence and focus on the patient's overall clinical condition. In contrast, non-experts used the anomalous evidence to evaluate diagnostic hypotheses and drive the decision making process. Expert physicians were also found to focus on situational aspects of the patient's condition to a greater extent than non-experts, occasionally employing recognitional strategies. Strategies for processing anomalous evidence were shown to relate to level of confidence in decision making. / The research has a number of important theoretical implications for the study of decision making and expertise in general and medical decision making in particular. A theoretical account of the role of expertise in complex decision making is provided which emphasizes the interaction between situation assessment and evaluative reasoning processes in the decision making of experts. In addition, the thesis provides empirical support for aspects of several emerging naturalistic models of decision making, and extends them to include greater consideration of processes involved in evaluation of evidence. Implications for education and design of decision support are discussed.

The transformation process involves genetic changes to cellular protooncogenes and tumor suppressor genes. The consequences of these genetic alterations are to confer a growth advantage to the cell. Three genetic mechanisms activate oncogenes or inactivate tumor suppressor genes in human neoplasms: (i) mutations, (ii) gene amplification, and (iii) chromosomal rearrangements. In many human cancers, tumor-specific chromosomal rearrangements are known to create chimeric products with the ability to transform cells. The EWS/WT1 protein is such a fusion product, resulting from a t(11;22) chromosomal translocation in Desmoplastic Small Round Cell Tumor (DSRCT), where 265 amino acids from the amino terminus of Ewing's sarcoma protein (EWS) are fused to zinc fingers II--IV of WT1. WT1 is a tumor suppressor gene expressed in the developing and adult urogenital system. Inactivation of WT1 has been correlated with initiation of Wilms' tumor (WT), a pediatric nephroblastoma, and Denys-brash syndrome, which is characterized by severe genitourinary disorders and WT. WT1 encodes a zinc-finger transcription factor belonging to the EGR (early growth response) family of Cys2-His2 zinc finger proteins and is mutated in 5--15% of sporadic WTs. WT1 recognizes the GC-rich motif, 5'-GCGGGGGCG-3 ', as well as a (TCC)n motif, albeit with different affinities, and can affect expression of a number of genes involved in the regulation of cell proliferation or differentiation. The t(11;22)(p13;g12) chromosomal translocation involved in DSRCT produces a chimeric protein containing the potential transcriptional activation domain of EWS fused to the DNA binding domain of WT1, suggesting that it may recognize similar DNA sequences as WT1. Since the DNA binding domains of WT1 and EWS/WT1 are structurally different, we have assessed the functional consequences of the EWS/WT1 fusion. We find that the EWS/WT1 protein has a higher binding affinity for the GC-rich WT1 binding site than the WT1 product

Replication-defective (E1+E3 deleted) human adenovirus vectors are promising means of therapeutic gene delivery to skeletal muscle cells. Since the tropism of adenovirus is non-selective, muscle-specific expression of systemically administered vectors can only be achieved by the use of a tissue-specific promoter/enhancer that is small enough to fit the insert capacity of the vector. We have generated a replication-defective adenovirus recombinant (AV) in which the reporter gene (firefly luciferase) was driven by a truncated (1.35 kb) muscle creatine kinase (MCK) promoter/enhancer. Highly efficient and muscle-specific transgene expression was demonstrated in immunodeficient mice after local injection of AV into muscles at early age. Luciferase levels produced by AVMCKlux compared favourably to those in parallel experiments from injection of AVRSVlux in which lux expression is driven by the ubiquitously active LTR sequences of RSV. In nonmuscle tissues (brain, liver, kidney, lung), the transgene expression was extremely low even though in these tissues in situ polymerase chain reaction showed as high an infectivity of the cells by the AV as in muscle, and high levels of expression were obtained with AVRSVlux. The relatively small size, the good efficiency and the muscle specificity of the MCK promoter/enhancer would make it ideal to drive the 6.3 kb (truncated) dystrophin cDNA in first generation AV (with a limited (8 kb) insert capacity) designed for gene therapy of Duchenne muscular dystrophy.

To improve our understanding of the potential function of the human growth hormone receptor (hGHR) during fetal development, the ontogeny of hGHR mRNA expression in human tissues was examined. In addition, portions of the hGHR gene regulatory regions were cloned and characterized. / Transcription of the hGHR gene was observed in multiple tissues from as early as the first trimester of human fetal life. Two isoforms of the mRNA coding region were identified, exon 3-retained or -deleted, and it was shown that expression of these two transcripts is individual-, but not tissue-, specific. In tissues from 117 individuals (4 weeks of fetal age to 64 years postnatal), predominant expression of the exon 3-deleted isoform occurred prior to 20 weeks of fetal life, suggesting that exon 3-deleted transcripts may be developmentally regulated. A six-fold increase in hepatic hGHR mRNA was observed postnatally, while the levels in kidney and intestine showed no significant developmental change and those in lung decreased six-fold postnatally. / This suggested that multiple gene promoters might be directing tissue-specific developmental changes in hGHR mRNA levels. Since heterogeneity in the 5 ' untranslated regions (5'UTR) of mRNAs can result from differential gene promoter usage, the expression patterns of three of the eight known 5'UTR variants (VI to V8, numbered according to their relative abundance in liver) were then investigated. Expression of V1, V3 and V4 was compared in fetal versus postnatal tissues, including hepatoblastomas and hepatocellular carcinomas. While V3 was detected in all tissues examined, the V1 and V4 variants were only present in normal postnatal liver specimens; they were not expressed in hepatic tumours. It was hypothesized that VI and V4 are derived by alternative splicing of a common gene transcript, while V3 synthesis is regulated by a distant and more widely transcribed gene promoter. / To identify DNA sequences regulating synthesis of the V1 and V4 5 'UTR variants, portions of the 5' flanking region of the hGHR gene were cloned. Four of the 5'UTR variant sequences were precisely placed in series (5' V7-V1-V4-V8 3') on a 3.8 kb XbaI-BsaAI genomic fragment. A transcriptional start site was identified upstream of the V1 sequence and found to generate, in postnatal liver, a long 5'UTR exon containing V1, V4 and V8 sequences. Evidence for a second liver-specific transcriptional start site, located upstream of V7, was also obtained. Alternative splicing of these gene products can result in several mRNA species, including the previously isolated V1, V4, V7 and V8 mRNA isoforms. Preliminary characterization of a 4.3 kb HindIII-XbaI genomic clone has revealed that the V3 as well as V2 sequences are located in series (5' V2-V3 3' ) in a distant genomic region, and computer analysis has suggested that there are transcriptional start sites upstream of both the V2 and V3 sequences. To construct a complete and continuous physical map of the hGHR gene, a Bacterial Artificial Chromosome (BAC) recombinant clone, encompassing more than 100 kb human genomic DNA and containing both V1- and V3-variant clusters, was isolated. Future characterization of the BAC clone will produce a complete map of the hGHR gene regulatory regions. / In summary, developmental changes in hGHR gene expression most likely reflect the maturation of an endocrine system but may also confer fetal-specific hGHR biological activity.

We assessed the effectiveness of bystander involvement and an emergency medical services (EMS) system on survival from out-of-hospital cardiac arrest in Montreal, Quebec (population of two million). A cohort of 1,697 cardiac arrests managed on-site by physicians was followed. Bystander telephone interviews were conducted for 1,147 (68%) of these cases. / Only 5% of patients (85/1,697) survived to hospital discharge. Collapse occurring after MD arrival, presenting cardiac rhythm and age of patient best predicted survival. Rapid access to physicians improved survival but rapid ambulance response time did not. Mean response times were 9.6 minutes for ambulances and 12.7 minutes for physicians. Time from call to dispatch explain these long response times. Bystander training was infrequent and it did not improve the system's response nor the survival of the patients. The reliability of bystander estimates of delays was weak. The relevance of survival rates from cardiac arrest as a marker of effectiveness in EMS systems evaluation is discussed.

Antiarrhythmic drugs, designed to prevent or suppress cardiac arrhythmias, may cause the worsening of an arrhythmia already present in a patient or provoke new and qualitatively different arrhythmias. Cardiotoxic effects of antiarrhythmic drugs may be rate-related or due to intoxication, and may lead to serious and potentially lethal ventricular arrhythmias. The goals of my research were (1) to study the mechanisms by which class IC antiarrhythmic drugs cause ventricular arrhythmias and (2) to explain the mechanisms of action of sodium salts in the reversal of class IC cardiotoxicity. / We used flecainide (F) as a prototype of its class to study the mechanism of action of class IC antiarrhythmic agents (AA). Flecainide is a potent sodium channel blocker producing a major effect on conduction velocity and a minor effect on refractoriness. In vitro studies have shown that F causes frequency-dependent reduction of phase 0 upstroke of cardiac action potential (V$ rm sb{max}$) in ventricular tissue. Flecainide, in the physiologic range of heart rates and at clinically relevant concentrations, may produce rate-dependent effects because of its relatively slow binding and unbinding kinetics. / We studied the effects of F in humans during exercise and showed that F produces an enhanced slowing of conduction when heart rate is increased, because of use-dependent sodium channel blockade. We demonstrated that a variety of class I AA produce use-dependent QRS prolongation in man with characteristic kinetics, which are similar to the kinetics of V$ sb{max}$ depression in vitro. We and others have reported proarrhythmic events associated with the rate-related cardiotoxicity of flecainide. Using a canine model of myocardial infarction, we showed the importance of previous myocardial infarction in flecainide-induced proarrhythmia. With epicardial mapping, we identified anisotropic reentry occurred in the mechanism for the ventricular arrhythmias. We reported that reentry occurred in the infarct zone around an arc of conduction block in the transverse direction. / Cardiotoxicity associated with F includes severe conduction slowing and life-threatening ventricular arrhythmias. Sodium salts have been found to reverse the effects caused by some class I antiarrhythmic agents (AA), but the mechanism of action is unknown. Using electrophysiological and biochemical studies, we investigated the role of extracellular sodium concentration ( (Na$ sp+ sb0$)) in modulating F's actions. In order to isolate the role of (Na$ sp+ sb0$), we used a range of (Na$ sp+ sb0$) and equimolar substitution with choline chloride. Our microelectrode experiments showed the ability of (Na$ sp+ sb0$) to modulate directly F's effects on the phase 0 upstroke (V$ rm sb{max}$). Our radioligand studies of displacement of ($ sp3$H) -batrachotoxinin A 20$ alpha$-benzoate ( ($ sp3$H) -BTXB) binding showed that this interaction was due to an effect of (Na$ sp+ sb0$ (on the binding of F to its receptor. We found that EC$ sb{50}$ values for depression of V$ rm sb{max}$ in electrophysiologic experiments and IC$ sb{50}$ values for flecainide displacement of ($ sp3$H) -BTXB in biochemical studies were highly correlated (r = 0.99). A limitation of our electrophysiologic study was the use of V$ rm sb{max}$ as an index of sodium current (I$ rm sb{Na}$). Using the whole-cell voltage clamp technique we found that increasing (Na$ sp+ sb0$) opposed F's blocking effect on I$ rm sb{Na}$, confirming the role of (Na$ sp+ sb0$ (. (Abstract shortened by UMI.)

Modified hemoglobin red blood cell substitutes have a number of potential areas of application. In some of these applications, it will be important to lessen the pro-oxidant effects of hemoglobin and potential free radical-mediated toxicity. This research introduces a novel modified hemoglobin that is based on intermolecularly crosslinking hemoglobin, superoxide dismutase and catalase (PolyHb-SOD-CAT) with the bifunctional agent, glutaraldehyde. Superoxide dismutase and catalase catalyze the breakdown of superoxide radical and hydrogen peroxide respectively. Studies of structural and functional parameters reveal that PolyHb-SOD-CAT retains superoxide dismutase and catalase enzymatic activity, and consists of a mixture of molecular species ranging in molecular size and protein composition. Circulation time studies of PolyHb-SOD-CAT in rats show that hemoglobin, superoxide dismutase and catalase possess longer circulatory half-lives as compared to the free forms of these proteins. Studies also show that PolyHb-SOD-CAT prevents the formation of methemoglobin, ferrylhemoglobin, hydroxyl radical, free iron, and lipid peroxidation. Ischemia-reperfusion studies using isolated perfused hindlimbs and intestine of rat show that PolyHb-SOD-CAT reduced the formation of hydroxyl radical compared to PolyHb. Altogether, these results suggest that PolyHb-SOD-CAT is a potentially safer modified hemoglobin oxygen carrier by virtue of its ability to detoxify reactive oxygen species, and reduced propensity to promote and participate in oxidative processes.

<p> A mobile phone based telemedicine study is developed to see how feasible phone usage is in selected health care applications. The research is divided into three different objectives. The first objective is to compile the technical characteristics of selected mobile phones from telemedicine perspective. The second objective is to develop techniques to acquire quality images of skin with mobile phones. Finally a smartphone based telemedicine application will be developed to assess skin cancer.</p>

Most authors recommend drawing the mechanical axis on a three-foot (90 cm) full leg length x-ray for accurate assessment of knee alignment. Three foot x-rays are difficult to perform and reproduce and involve undue radiation to the gonads. The purpose of this project is to propose a new radiographic technique whereby the mechanical axis of the knee can be assessed on a short A/P x-ray of the entire tibia. / Methodology. 21 normal adults and 25 patients with malaligned knees were investigated in the following manner--the patient was x-rayed in standing position with the legs positioned exactly parallel to one another and vertical to the floor. Under these circumstances, the ankles were apart by a distance (distance F$ sb1$) equal to the distance between the femoral heads (distance F). The mechanical axes were hence parallel to one another and parallel to the long axis of the x-ray cassette and vertical to the floor. Two separate x-rays were taken, a three-foot (90cm) long x-ray and a short x- ray of the entire tibia. The mechanical axis was determined on the 90 cm, three-foot long x-ray. / A vertical line drawn on the short x-ray starting from the centre of the ankle and extended upwards and parallel to the long axis of the x-ray cassette could accurately identify the mechanical axis of the knee using either technique. (Fig. 1) / The technique has been called the "Parallel Mechanical Axes X-ray Technique". It has been validated and it will be demonstrated that such an x-ray technique: (1) Standardizes positioning of the lower extremities. (2) Is a precise, easily controllable method to assess knee alignment. (3) A short x-ray of the entire tibia is sufficient, thus reducing the cost of x-rays by 50%. (4) Obviates the need to visualize the pelvis thus minimizing net radiation exposure. (5) May be used in clinics and smaller hospitals, since it requires simple and inexpensive x-ray facilities.

Nonvalidated practices are characterized by a therapeutic intent and a relative lack of evidence to support their adoption into the practice of medicine. They occupy a continuum of progressive departures from the standard of care, bounded on the one extreme by validated practices and on the other by research. Presently, nonvalidated practices are performed largely at the discretion of physicians, and this approach has been justified by appeal to the notions of professional autonomy and societal beneficence. Current guidelines do not require any special form of monitoring of nonvalidated practices. However, the principle of non-maleficence favours the adoption of a novel monitoring system which would assure the protection of patients and society. This novel monitoring system should be based on a review which is proportionate, prospective, and primarily local but with an important national element. As well, such a system should be based largely on the existing hospital practice committees.